Novel process and intermediates useful in the preparation of sympathomimetic amines

ABSTRACT

The invention relates to a novel process and novel intermediates useful in the preparation of sympathomimetic amines. The pharmacologically useful final products, which are acyl derivatives of mono- and dihydroxy aromatic amines (e.g., catechol amines) can be prepared in optically active or racemic form by reacting the corresponding mono- or dihydroxy aromatic amine with a reagent capable of forming the N-tert-butoxycarbonyl derivative thereof; reacting the novel intermediate thus obtained with an acyloxymethyl chloride to afford the corresponding novel mono- or diacylated N-protected aromatic amine; and removing the N-protecting group therefrom.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention is directed to a novel synthetic process forpreparing esters of catechol amines and other sympathomimetic amines inoptically active or racemic form, and to novel N-tert-butoxycarbonylintermediates useful in the subject process.

2. Description of the Prior Art

U.S. Pat. Nos. 3,809,714, 3,825,583, 3,839,584, 3,868,461, 3,959,485,3,966,749, 3,908,017, 4,035,405, 4,088,783, 4,145,441 and 4,158,005, allin the name of the instant assignee, disclose a number ofsympathomimetic amine derivatives within the general formula (I) setforth hereinbelow, and nontoxic pharmaceutically acceptable acidaddition salts thereof. The compounds of formula (I) and their salts areuseful in the treatment of conditions responsive to sympathomimeticamines, e.g., glaucoma, asthma and nasal congestion.

Prior art methods for the preparation of compounds within the scope ofthe formula (I) below generally have provided the compound in the formof a racemic mixture, i.e., a mixture containing both the biologicallyactive and the biologically inactive isomer. Normally, the compounds offormula (I) have been administered in the form of a racemic mixture, asthe means to separate the optically active, biologically active isomersfrom their racemic mixtures are tedious and expensive. In fact,resolution of the racemic mixtures of many of the compounds of formula(I) has not been reported in the literature.

Consequently, it is apparent that a need exists for a means of directlysynthesizing the optically active, biologically active forms of thecompounds of formula (I), thus avoiding the necessity of first obtainingthe racemic mixture and then either resolving the racemic mixture andadministering the optically and biologically active isomer thereof, orelse, as is more frequently the case, administering the racemic mixtureitself. In the latter case, it is apparent that the dosage amount of aracemic mixture which would be required to achieve therapeusis would bemuch greater than that required if only the optically active,biologically active isomer were administered.

SUMMARY OF THE INVENTION

Accordingly, the present invention has as an object a novel process forthe preparation of a compound of the general formula ##STR1## wherein R₁is H or alkyl of 1 to 7 carbon atoms; R₂ is H, alkyl of 1 to 7 carbonatoms, or -alkylene ##STR2## wherein m is zero or one, the alkyleneportion contains 1 to 5 carbon atoms, and X is H or --OR'₄ wherein R'₄is identical to R₄ as defined below; R₃ is H, Cl, --CH₂ OH or --OR"₄wherein R"₄ is identical to R₄ as defined as below; and R₄ is an acylradical; or a nontoxic pharmaceutically acceptable acid addition saltthereof; which comprises:

(a) reacting a compound of the general formula ##STR3## wherein R₁ isdefined as above; R is H, Cl, --CH₂ OH or --OH; and R₅ is H, alkyl of 1to 7 carbon atoms, or ##STR4## wherein m and alkylene are defined asabove and X' is H or --OH; with a reagent capable of forming theN-tert-butoxycarbonyl derivative thereof;

(b) reacting the resultant N-tert-butoxycarbonyl derivative of theformula ##STR5## wherein R, R₁ and R₅ are defined as above, with anacyloxymethyl chloride of the formula

    R.sub.4 OCH.sub.2 Cl                                       (IV)

wherein R₄ is an acyl radical, in an organic solvent in the presence ofa base; and

(c) removing the tert-butoxycarbonyl protecting group from the resultantcompound of the formula ##STR6## wherein R₁, R₂, R₃, and R₄ are definedas above.

The novel process for the preparation of compounds of formula (I) andtheir nontoxic pharmaceutically acceptable acid addition salts which isset forth above provides the desired compounds in optically active or inracemic form, depending on the particular starting material employed.Said process further provides novel intermediates useful in thepreparation of the compounds of formula (I), said novel intermediateshaving the structural formulas (III) and (V) set forth above.

DETAILED DESCRIPTION OF THE INVENTION

With respect to the various groups encompassed by the generic terms usedhere and throughout this specification, the following definitions andexplanations are applicable:

The alkyl groups encompassed by R₁ include straight and branched-chainradicals containing the indicated number of carbon atoms, with methyland ethyl being preferred.

The alkyl groups encompassed by R₂ and R₅ likewise can be straight orbranched-chain containing the indicated number of carbon atoms. In thecase of the R₂ and R₅ substituents, preferred alkyl groups are methyl,isopropyl and tert-butyl.

When R₂ is an ##STR7## or when R₅ is an ##STR8## the alkylene bridge canbe a straight or branched-chain group of the type C_(n) H_(2n), whereinn is 1 to 5, e.g. ethylene, 1,2-propylene and 1,3-butylene.

With respect to the acyl groups represented by the R₄ term, it is to benoted that at each occurrence R₄ preferably represents an acyl radicalselected from the group consisting of alkanoyl having 1 to 22 carbonatoms; alkenoyl having one or two double bonds and having 4 to 22 carbonatoms; ##STR9## having a total of 4 to 10 carbon atoms of which 3 to 7are ring carbon atoms in the cycloalkyl portion and wherein n is zero,one or two; phenoxyacetyl; naphthalenecarbonyl; pyridinecarbonyl; and##STR10## wherein n is zero, one or two and phenyl is unsubstituted oris substituted by 1 to 3 alkyl each having 1 to 4 carbon atoms, alkoxyhaving 1 to 4 carbon atoms, halo, trifluoromethyl, dialkylamino having 2to 8 carbon atoms or alkanoylamino having 1 to 6 atoms.

When R₄ is alkanoyl containing 1 to 22 carbon atoms, there are includedboth unbranched and branched alkanoyl, for example, formyl, acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, 2-methylbutanoyl,pivalyl (pivaloyl), 3-methylpentanoyl, 3,3-dimethylbutanoyl,2,2-dimethylpentanoyl, docosanyl and 7,7-dimethyloctanoyl. Branchedalkanoyl groups are generally preferred, an especially preferred groupbeing pivaloyl.

When R₄ is alkenoyl having one or two double bonds and having 4 to 22carbon atoms, there are included, for example, crotonyl, 9-octadecenoyl,2,5-hexadienoyl, 3,6-octadienoyl, 10,13-octadecadienoyl and5,13-docosadienoyl.

When R₄ is ##STR11## there are included cycloalkanecarbonyl andcycloalkanealkanoyl groups wherein the cycloalkane portion canoptionally bear 1 or 2 alkyl groups as substituents, e.g.,cyclopropanecarbonyl, 1-methylcyclopropanecarbonyl, cyclopropaneacetyl,alpha-methylcyclopropaneacetyl, 1-methylcyclopropaneacetyl,2-amylcyclopropaneacetyl, cyclopropanepropionyl,alpha-methylcyclopropanepropionyl, 2-isobutylcyclopropanepropionyl,2-hexylcyclopropanecarbonyl, cyclobutanepropionyl,2-methylcyclobutanecarbonyl, 1,3-dimethylcyclobutanecarbonyl,3,3-dimethylcyclobutanecarbonyl, cyclobutaneacetyl,2,2-dimethyl-3-ethylcyclobutaneacetyl, cyclobutanepropionyl,cyclopentanecarbonyl, 1-methyl-3-isopropylcyclopentanecarbonyl,cyclopentanepropionyl, cyclohexanecarbonyl, cyclohexaneacetyl,4-methylcyclohexaneacetyl, cycloheptanecarbonyl,4-methylcycloheptaneacetyl, and cycloheptanepropionyl.

When R₄ is ##STR12## there are included, for example, benzoyl,phenylacetyl, alpha-phenylpropionyl, beta-phenylpropionyl, p-toluyl,m-toluyl, o-toluyl, o-ethylbenzoyl, p-tert-butylbenzoyl,3,4-dimethylbenzoyl, 2-methyl-4-ethylbenzoyl, 2,4,6-trimethylbenzoyl,m-methylphenylacetyl, p-isobutylphenylacetyl,beta-(p-ethylphenyl)propionyl, p-anisoyl, m-anisoyl, o-anisoyl,m-isopropoxybenzoyl, p-n-butoxybenzoyl, 3-methoxy-4-ethoxybenzoyl,3,4,5-trimethoxybenzoyl, 2,4,6-triethoxybenzoyl, p-methoxyphenylacetyl,m-isobutoxyphenylacetyl, 3,4-diethoxyphenylacetyl,beta-(3,4,5-trimethoxyphenyl)propionyl, o-iodobenzoyl, m-bromobenzoyl,p-chlorobenzoyl, p-fluorobenzoyl, 2-bromo-4-chlorobenzoyl,2,4,6-trichlorobenzoyl, p-chlorophenylacetyl,alpha-(m-bromophenyl)propionyl, p-trifluoromethylbenzoyl,2,4-di(trifluoromethyl)benzoyl, m-trifluoromethylphenylacetyl,beta-(p-trifluoromethylphenyl)propionyl, 2-methyl-4-methoxybenzoyl,3-chloro-4-ethoxybenzoyl, beta-(3-methyl-4-chlorophenyl)propionyl,p-dimethylaminobenzoyl, m-diethylaminobenzoyl, p-dibutylaminobenzoyl,p-(N-methyl-N-ethylamino)benzoyl, o-acetamidobenzoyl,m-propionamidobenzoyl, p-hexanoylaminobenzoyl,3-chloro-4-acetamidophenylacetyl, and p-acetamidophenylpropionyl.

When R₄ is naphthalenecarbonyl, there are included 1-naphthalenecarbonyland 2-naphthalenecarbonyl.

When R₄ is pyridinecarbonyl, there are included picolinoyl(2-pyridinecarbonyl), nicotinoyl (3-pyridinecarbonyl), and isonicotinoyl(4-pyridinecarbonyl).

Finally, the term "nontoxic pharmaceutically acceptable acid additionsalt" as used herein generally includes the nontoxic acid addition saltsof selected compounds of formula (I), formed with nontoxic inorganic ororganic acids. For example, the salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic,phosphoric, nitric and the like; and the salts prepared from organicacids such as acetic, propionic, succinic, glycollic, stearic, lactic,malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic, fumaric,sulfonic, toluenesulfonic, and the like.

By selecting the appropriate reactants for the ultimte specie desired,the compounds of formula (I) are conveniently prepared in accordancewith the synthetic scheme of the present invention.

The compounds of formula (I) which are prepared by the process of thepresent invention find therapeutic application in the treatment ofwarm-blooded animals (e.g., humans) in the management of asthma, asdecongestants, vasoconstrictors, mydriatic agents and anti-glaucomatousagents, and in the treatment of other conditions responsive tosympathomimetic amines. Upon administration, the compounds of formula(I) will enzymatically "cleave" and release the parent phenol, thetherapeutically active moiety thereof. Thus, in a preferred embodiment,the present invention provides a novel process and novel intermediatesto acylated derivatives of such known sympathomimetic amines asepinephrine, isoproterenol, norepinephrine, phenylephrine, metaraminol,metaproterenol, terbutaline, nordeferin, colterol, deterenal, albuteroland fenoterol, and the nontoxic pharmaceutically acceptable acidaddition salts thereof. The instant process and intermediates areespecially preferred when they provide acylated derivatives of theaforementioned sympathomimetic amines wherein the acyl group is alkanoylas hereinbefore defined, most especially when the alkanoyl group isbranched, e.g., pivaloyl. Also, while it is a particular and surprisingadvantage of the present process that the stereochemical integrity ofthe starting material of formula (II) can be maintained throughout theinstant reaction scheme, thus affording an attractive synthetic route tothe optically and biologically active isomers of formula (I), it will beapparent to those skilled in the art that the process of the inventioncan be employed equally as well in the production of racemic mixtures asin the preparation of optically active isomers. As such, the scope ofthe present invention extends to this feature as well.

Turning now to the individual steps of the novel process of the presentinvention, it is noted that step (a), which provides novelN-tert-butoxycarbonyl derivatives of formula (III) above, proceeds byreacting a starting material of formula (II) with a reaent capable offorming the N-tert-butoxycarbonyl derivative thereof. Such reagents arewell-known to those skilled in the art of peptide synthesis, where theyare widely used to protect the amino group of amino acids. Typicalreagents include t-butylazidoformate, di(t-butyl)dicarbonate and thelike, with t-butylazidoformate being a preferred reagent. Obviously, thechoice of solvent and other reaction conditions will depend upon theparticular reagent employed, suitable solvents and conditions beingapparent to those skilled in the art of peptide synthesis. In the caseof t-butylazidoformate, the reaction can be conveniently conducted inpyridine, preferably in the presence of triethylamine, although adioxane/magnesium oxide solvent system may be employed in place of thepyridine/triethylamine. Time and temperature depend on the particularstarting material of formula (II), the particular reagent and theparticular sol vent system employed. Generally speaking, heatingaccelerates the reaction, which is typically complete in 16 hours orless at a temperature of 40°- 90° C. The reaction is convenientlyconducted at atmospheric pressure, preferably under nitrogen.

With respect to step (b) of the instant process, i.e. reacting a novelN-tert-butoxycarbonyl derivative of formula (III) with an acyloxymethylchloride of formula (IV), it is to be noted that this reaction issurprising in two respects, namely: (1) that the phenolic hydroxygroup(s) of the compound of formula (III) react to form thecorresponding ester group(s), not the acyloxymethyl ether group(s) aswould normally be expected; and (2) that the stereochemical integrity ofthe starting material is maintained during the acylation. The reactionis conducted in an organic solvent in the presence of a base. Suitablebase/solvent combinations are those which are known to neutralizephenolic hydroxy groups without causing undesirable side reactions suchas oxidation. Choice of particular solvent and base will depend upon thenature of the starting material of formula (III). For example, in thecase of catechol amines, e.g. derivatives of epinephrine, a potassiumcarbonate/acetone combination has been found to be highly desirable. Onthe other hand, when the starting material of formula (III) is not acatechol, e.g. a 3,5-dihydroxyphenol or a monohydroxyphenol, then astronger base such as potassium carbonate may be used in an appropriatesolvent, e.g. methanol. Time, temperature and pressure are not criticalfactors. The reaction is conveniently conducted at atmosphereicpressure, under nitrogen. Time and temperature vary with the particularstarting materials employed. Typical reaction times are 30 minutes to 4days, while typical temperatures are from room temperature to reflux.

With respect to step (c) of the process of the present invention, i.e.removal of the amino protecting group from the compound of formula (V),it is to be noted that this reaction is analogous to those well-known inthe art of peptide synthesis. Thus, removal of the protecting group canbe achieved by any means suitable for removing a tert-butoxycarbonylgroup without affecting the remaining portions of the molecule, forexample, by use of trifluoroacetic acid in dichloromethane, or hydrogenchloride in ethyl acetate, at room temperature or, preferably, belowroom temperature, for a short period of time (e.g. 15 minutes to 2hours). The use of HCl in ethyl acetate is a preferred means of removingthe protecting group, since it affords the compound of formula (I) inthe form of its highly desirable hydrochloride salt. However, the saltformed by the acid which is used to remove the protecting group can bereadily neutralized to the free base of formula (I) and then, ifdesired, reacted with an appropriate acid to form the correspondingnontoxic, pharmaceutically acceptable acid addition salt. Alternatively,the salt obtained after removal of the protecting group, e.g. thehydrochloride, can be subjected to an ion exchange procedure in order toobtain a different, nontoxic, pharmaceutically acceptable salt offormula (I).

Without further elaboration, it is believed that one of ordinary skillin the art can, using the preceding description, utilize the presentinvention to its fullest extent. Consequently, the following preferredspecific embodiments are to be construed as merely illustrative and notlimitative of the remainder of the specification and claims in any waywhatsoever.

EXAMPLE 1 Preparation ofR-3,4-Dihydroxy-α-[(N-methyl-N-tert-butoxycarbonyl)aminomethyl]benzylalcohol

18.3 G (0.10 mole) of R-(-)-epinephrine and 14.3 g (0.10 mole) oft-butylazidoformate [L. A. Carpino et al, Organic Synthesis, CollectiveVol. 5, H. E. Baumgarten, ed., John Wiley and Sons, New York, p. 157(1973)] were combined with 13.9 ml (0.1 mole) of triethylamine in 25 mlof pyridine. The reaction mixture was stirred under nitrogen at 60° C.for approximately 16 hours. The solvent was evaporated from theresultant solution and the residue was taken up in 200 ml of etheer. Theether solution was washed successively with 10% hydrochloric acid,saturated sodium bicarbonate solution, water, and saturated sodiumchloride solution, then was dried over magnesium sulfate and evaporatedto give 14.6 g of a reddish brown glass. IR (CHCl₃): 3540 (free OH),3360 (OH), ##STR13## NMR (CDCL₃ TMS): δ1.40 (s, 9H, C(CH₃)₃), 2.73 (s,3H, NCH₃), 3.33 (broad s, 2H, --CH₂ N), 4.70 (broad s, 1H, CH--OH), 6.70(broad s, 2H, aromatic), 6.80 (broad s, 1H, aromatic).

Similarly prepared from dl-epinephrine, dl-isoproterenol,l-isoproterenol, l-norepinephrine, l-phenylephrine, l-metaraminol,dl-metaproterenol and dl-terbutaline are the t-butoxycarbonylderivatives thereof, namelydl-3,4-dihydroxy-α-[(N-methyl-N-tert-butoxycarbonyl)aminomethyl]benzylalcohol;dl-3,4-dihydroxy-α-[(N-isopropyl-N-tert-butoxycarbonyl)aminomethyl]benzylalcohol;1-3,4-dihydroxy-α-[(N-isopropyl-N-tert-butoxycarbonyl)aminomethyl]benzylalcohol; l-α-[(N-tert-butoxycarbonyl)aminomethyl]3,4-dihydroxybenzylalcohol;l-m-hydroxy-α-[(N-methyl-N-tert-butoxycarbonyl)aminomethyl]benzylalcohol; l-α-[1-α-[1-(N-tert-butoxycarbonyl)aminoethyl]-m-hydroxybenzylalcohol;dl-3,5-dihydroxy-α-[(N-isopropyl-N-tert-butoxycarbonyl)aminomethyl]benzylalcohol; anddl-α-[(N-tert-butyl-N-tert-butoxycarbonyl)aminomethyl]-3,5-dihydroxybenzoylalcohol, respectively.

EXAMPLE 2 Preparation ofR-α-[(N-Methyl-N-tert-butoxycarbonyl)aminomethyl]benzyl alcohol3,4-dipivalate

To 100 ml of dry acetone were added 2.6 g (0.0095 mole) ofR-3,4-dihydroxy-α-[(N-methyl-N-tert-butoxycarbonyl)aminomethyl]benzylalcohol, 14.3 g (0.095 mole) of chloromethyl pivalate, and 2.6 g (0.0095mole) of potassium carbonate. The reaction mixture was stirredovernight, then filtered. The filtrate was evaporated to dryness and theresulting oil was dissolved in a small amount of petroleum ether (b.p.30°-60° C.). That solution was then chromatographed on a silica gelcolumn. Elution with 2 column volumes of petroleum ether (b.p. 30°-60°C.) gave 7.0 g of recovered chloromethyl pivalate. The desired crudeproduct was obtained by elution with 2 column volumes of ethyl acetate,followed by evaporation of solvent. The crude material wasrechromatographed on silica gel and eluted with chloroform to give apale yellow oil which crystallized upon standing. That solid wasrecrystallized from petroleum ether (b.p. 30°-60° C.) to give 1.9 g ofproduct, mp 103°-105° C. Analysis: Cal'd for C₂₄ H₃₇ NO₇ : C, 63.83; H,8.26; N, 3.10. Found: C, 63.95; H, 8.50; N, 2.99.

In a similar manner, the t-butoxycarbonyl derivatives of dl-epinephrine,dl-isoproterenol, l-isopropterenol, l-norepinephrine, l-phenylephrine,l-metaraminol, dl-metaproterenol and dl-terbutaline are reacted withchloromethyl pivalate to afford the corresponding t-butoxycarbonylpivalates and dipivalates, i.e.,dl-α-[(N-methyl-N-tert-butoxycarbonyl)aminomethyl]benzyl alcohol3,4-dipivalate;dl-α-[(N-isopropyl-N-tert-butoxycarbonyl)aminomethyl]benzyl alcohol3,4-dipivalate;l-α-[(N-isopropyl-N-tert-butoxycarbonyl)aminomethyl]benzyl alcohol3,4-dipivalate, l-α-[(N-tert-butoxycarbonyl)aminomethyl]benzyl alcohol3,4-dipivalate; l-α-[(N-methyl-N-tert-butoxycarbonyl)aminomethyl]benzylalcohol 3-pivalate; l-α-[1-(N-tert-butoxycarbonyl)aminoethyl]benzylalcohol 3-pivalate;dl-α-[(N-isopropyl-N-tert-butoxycarbonyl)aminomethyl]benzyl alcohol3,5-dipivalate; anddl-α-[(N-tert-butyl-N-tert-butoxycarbonyl)aminomethyl]benzyl alcohol3,5-dipivalate, respectively.

EXAMPLE 3 Preparation of R-(-)-α-[(Methylamino)methyl]benzyl alcohol3,4-dipivalate hydrochloride

A solution of 400 mg ofR-α-[(N-methyl-N-tert-butoxycarbonyl)aminomethyl]benzyl alcohol3,4-dipivalate in 10 ml of ethyl acetate was cooled to 4° C. in an icebath and dry nitrogen was bubbled into the solution. After cooling,hydrogen chloride gas was bubbled into the solution until thin layerchromatography indicated that no unreacted starting material remained(approximately 1 hour). Solvent was removed from the reaction mixture togive a white foam. That residue was crystallized from a 1:1 mixture ofacetone and hexane to afford 300 mg of white crystals, m.p. 155°-157°C., [α]_(D) ²⁵ =-27.4 (C=1.25, H₂ O). Analysis: Cal'd for C₁₉ H₃₀ ClNO₅: C, 58.83; H, 7.80; N, 3.61. Found: C, 58.50; H, 7.95; N, 3.36.

In a similar manner, substitution of the products named in the secondparagraph of Example 2 in the procedure detailed above, or its obviouschemical equivalent, affords the following products:dl-α-[(methylamino)methyl]benzyl alcohol 3,4-dipivalate hydrochloride;dl-α-[(isopropylamino)methyl]benzyl alcohol 3,4-dipivalatehydrochloride; l-α-[(isopropylamino)methyl]benzyl alcohol 3,4-dipivalatehydrochloride; l-α-(aminomethyl)benzyl alcohol 3,4-dipivalatehydrochloride; l-α-[(methylamino)methyl]benzyl alcohol 3-pivalatehydrochloride; l-α-(1-aminoethyl)benzyl alcohol 3-pivalate;dl-α-[(isopropylamino)methyl]benzyl alcohol 3,5-dipivalate; anddl-α-[(tert-butylamino)methyl]benzyl alcohol 3,5-dipivalate,respectively.

While the invention has been described in terms of various preferredembodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions and additions may be madewithout departing from the spirit thereof. Accordingly, it is intendedthat the scope of the present invention be limited solely by the scopeof the following claims.

What I claim is:
 1. A process for the preparation of a compound of theformula ##STR14## wherein R₁ is H or alkyl of 1 to 7 carbon atoms; R₂ isH, alkyl of 1 to 7 carbon atoms, or ##STR15## wherein m is zero or one,the alkylene portion contains 1 to 5 carbon atoms, and X is H or --OR₄ 'wherein R₄ ' is identical to R₄ as defined below; R₃ is H, Cl, --CH₂ OHor --OR₄ " wherein R₄ " is identical to R₄ as defined below; and R₄ isan acyl radical; or a nontoxic pharmaceutically acceptable acid additionsalt thereof; which comprises:(a) reacting a compound of the formula##STR16## wherein R₁ is defined as above; R is H, Cl, --CH₂ OH or --OH;and R₅ is H, alkyl of 1 to 7 carbon atoms, or ##STR17## wherein m andalkylene are defined as above and X' is H or --OH; with a reagentcapable of forming the N-tert-butoxycarbonyl derivative thereof; (b)reacting the resultant N-tert-butoxycarbonyl compound of the formula##STR18## wherein R, R₁ and R₅ are defined as above, with anacyloxymethyl chloride of the formula

    R.sub.4 OCH.sub.2 Cl                                       (IV)

wherein R₄ is an acyl radical, in an organic solvent in the presence ofa base, to effect acylation of all phenolic hydroxy groups in saidcompound of formula (III); and (c) removing the tert-butoxycarbonylprotecting group from the resultant compound of the formula ##STR19##wherein R₁, R₂, R₃ and R₄ are defined as above.
 2. A process accordingto claim 1 wherein R₄ is an acyl radical selected from the groupconsisting of alkanoyl having 1 to 22 carbon atoms; alkenoyl having oneor two double bonds and having 4 to 22 carbon atoms; ##STR20## having atotal of 4 to 10 carbon atoms of which 3 to 7 are ring carbon atoms inthe cycloalkyl portion and wherein n is zero, one or two; phenoxyacetyl;1-naphthalenecarbonyl; 2-naphthalenecarbonyl; 2-pyridinecarbonyl;3-pyridinecarbonyl; 4-pyridinecarbonyl; and ##STR21## wherein n is zero,one or two and phenyl is unsubstituted or is substituted by 1 to 3 alkyleach having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms,halo, trifluoromethyl, dialkylamino having 2 to 8 carbon atoms oralkanoylamino having 1 to 6 carbon atoms.
 3. A process according toclaim 1 wherein R₁ is hydrogen.
 4. A process according to claim 1wherein R and R₃ are each hydrogen.
 5. A process according to claim 1wherein R is --OH and R₃ is --OR₄ " wherein R₄ " is as defined inclaim
 1. 6. A process according to claim 1 wherein R₁ is methyl orethyl.
 7. A process according to claim 1 wherein R₂ and R₅ are eachhydrogen.
 8. A process according to claim 1 wherein R₂ and R₅ are eachalkyl of 1 to 7 carbon atoms.
 9. A process according to claim 1 whereinR₂ and R₅ are each methyl, isopropyl or tert-butyl.
 10. A processaccording to claim 1 wherein R₂ and R₅ are ##STR22## respectively,wherein alkylene, m, X and X' are as defined in claim
 1. 11. A processaccording to claim 10 wherein alkylene is ethylene, 1,2-propylene or1,3-butylene.
 12. A process according to claim 1 wherein the product offormula (I) is an optically and biologically active isomer.
 13. Aprocess according to claim 1 wherein the product of formula (I) is aracemic mixture.
 14. A process according to claim 1 wherein the startingmaterial of formula (II) is selected from the group consisting ofepinephrine, isoproterenol, norepinephrine, phenylephrine, metaraminol,metaproterenol, terbutaline, nordeferin, colterol, deterenal, albuteroland fenoterol.
 15. A process according to claim 1 wherein the startingmaterial of formula (II) is R-(-)-epinephrine.
 16. A process accordingto claim 1 wherein the reagent employed in step (a) ist-butylazidoformate.
 17. A process according to claim 16 wherein thestep (a) reaction is conducted in pyridine.
 18. A process according toclaim 17 wherein the step (a) reaction is conducted in the presence oftriethylamine.
 19. A process according to claim 18 wherein the step (a)reaction is conducted at a temperature of from about 40 to about 90° C.20. A process according to claim 1 wherein the acyloxymethyl chlorideemployed in step (b) is an alkanoyloxymethyl chloride wherein thealkanoyl group contains 1 to 22 carbon atoms.
 21. A process according toclaim 20 wherein the acyloxymethyl chloride employed in step (b) ischloromethyl pivalate.
 22. A process according to claim 20 or 21 whereinthe organic solvent employed in step (b) is acetone.
 23. A processaccording to claim 20 or 21 wherein the base is potassium carbonate. 24.A process according to claim 22 wherein the base is potassium carbonate.25. A process according to claim 1 wherein in step (c) thetert-butoxycarbonyl protecting group is removed by use of a reagentwhich affords the desired compound of formula (I) in the form of anontoxic, pharmaceutically acceptable acid addition salt.
 26. A processaccording to claim 1 wherein in step (c) the tert-butoxycarbonylprotecting group is removed by use of hydrogen chloride in ethylacetate.
 27. A process for the preparation of a compound of the formula##STR23## wherein R₁ is H or alkyl of 1 to 7 carbon atoms, R₂ is H,alkyl of 1 to 7 carbon atoms, or ##STR24## wherein m is zero or one, thealkylene portion contains 1 to 5 carbon atoms, and X is H or --OR₄ 'wherein R₄ ' is identical to R₄ as defined below; R₃ is H, Cl, --CH₂ OHor --OR₄ " wherein R₄ " is identical to R₄ as defined below; and R₄ isan acyl radical; which comprises reacting an N-tert-butoxycarbonylcompound of the formula ##STR25## wherein R₁ is defined as above; R isH, Cl, --CH₂ OH or --OH; and R₅ is H, alkyl of 1 to 7 carbon atoms; or##STR26## wherein m and alkylene are defined as above and X' is H or--OH; with an acyloxymethyl chloride of the formula

    R.sub.4 OCH.sub.2 Cl                                       (IV)

wherein R₄ is an acyl radical, in an organic solvent, in the presence ofa base, to effect acylation of all phenolic hydroxy groups in saidcompound of formula (III).
 28. A process according to claim 27 whereinR₄ is an acyl radical selected from the group consisting of alkanoylhaving 1 to 22 carbon atoms; alkenoyl having one or two double bonds andhaving 4 to 22 carbon atoms; ##STR27## having a total of 4 to 10 carbonatoms of which 3 to 7 are ring carbon atoms in the cycloalkyl portionand wherein n is zero, one or two; phenoxyacetyl; 1-naphthalenecarbonyl;2-naphthalenecarbonyl; 2-pyridinecarbonyl; 3-pyridinecarbonyl;4-pyridinecarbonyl; and ##STR28## wherein n is zero, one or two andphenyl is unsubstituted or is substituted by 1 to 3 alkyl each having 1to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, halo,trifluoromethyl, dialkylamino having 2 to 8 carbon atoms oralkanoylamino having 1 to 6 carbon atoms.
 29. A process according toclaim 27 wherein R and R₃ are each hydrogen.
 30. A process according toclaim 27 wherein R is --OH and R₃ is --OR₄ " wherein R₄ " is as definedin claim
 27. 31. A process according to claim 27 wherein R₄ is alkanoylhaving 1 to 22 carbon atoms.
 32. A process according to claim 27 whereinR₁ is hydrogen.
 33. A process according to claim 27 wherein R₁ is methylor ethyl.
 34. A process according to claim 27 wherein R₂ and R₅ are eachhydrogen.
 35. A process according to claim 27 wherein R₂ and R₅ are eachalkyl of 1 to 7 carbon atoms.
 36. A process according to claim 27wherein R₂ and R₅ are each methyl, isopropyl or tert-butyl.
 37. Aprocess according to claim 27 wherein R₂ and R₅ are ##STR29##respectively, wherein alkylene, m, X and X' are as defined in claim 27.38. A process according to claim 37 wherein alkylene is ethylene,1,2-propylene or 1,3-butylene.
 39. A process according to claim 27wherein the starting material of formula (III) is selected from thegroup consisting of the N-tert-butoxycarbonyl derivatives ofepinephrine, isoproterenol, norepinephrine, phenylephrine, metaraminol,metaproterenol, terbutaline, nordeferin, colterol, deterenal, albuteroland fenoterol.
 40. A process according to claim 27 wherein the startingmaterial of formula (III) is the N-tert-butoxycarbonyl derivative ofR-(-)-epinephrine.
 41. A process according to claim 27 wherein theacyloxymethyl chloride is chloromethyl pivalate.
 42. A process accordingto claim 31 or 41 wherein the organic solvent employed is acetone.
 43. Aprocess according to claim 31 or 41 wherein the base is potassiumcarbonate.
 44. A process according to claim 42 wherein the base ispotassium carbonate.